The demand for enantiomerically pure compounds has grown rapidly in recent years. One important use for such chiral, non-racemic alcohols is as intermediates for synthesis in the pharmaceutical industry. For instance, it has become increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. These advantages include fewer side effects and greater potency often associated with enantiomerically pure compounds.
Traditional methods of organic synthesis were often optimized for the production of racemic materials. The production of enantiomerically pure material has historically been achieved in one of two ways: use of enantiomerically pure starting materials derived from natural sources (the so-called “chiral pool”); and the resolution of racemic mixtures by classical techniques. Each of these methods has serious drawbacks, however. The chiral pool is limited to compounds found in nature, so only certain structures and configurations are readily available. Resolution of racemates, which requires the use of resolving agents, may be inconvenient and time-consuming.
Catalytic asymmetric synthesis is providing chemists with new and powerful tools for the efficient synthesis of complex molecules. While many of the catalytic systems are metal-based and rely on chiral Lewis acid and organometallic redox-based catalysis, increasing numbers of asymmetric reactions are catalyzed by chiral nucleophiles, building on the vast assortment of situations in nature in which nucleophiles play pivotal roles. For leading references, see: (a) In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999; (b) In Asymmetric Catalysis in Organic Synthesis, Noyori, R., Ed.; Wiley: New York, 1994; (c) In Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; VCH: New York, 2000; (d) Acc. Chem. Res. 2000, 33, 323. (e) Groger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529; (f) Pierre, J.-L. Chem. Soc. Rev. 2000, 29,251-257. (g) Roberts, B. P. Chem Soc. Rev. 1999, 28, 25. Chiral amines play a central role in this expanding area of asymmetric catalysis. Although chiral amines have been utilized extensively as chiral ligands, they have also shown great promise in catalyzing a broad range of asymmetric transformations, yielding optically enriched products in high selectivity and yield that may not be accessible through alternative asymmetric technology. Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis; Wiley & Sons: New York, 1995.
The cinchona alkaloids were the first chiral amines to be used in asymmetric catalysis, most notably in the pioneering work of Pracejus from the 1960s on disubstituted ketene alcoholysis. Cinchona alkaloids also possess a rich and colorful history that is rooted in natural products and pharmaceutical chemistry. Turner, R. B.; Woodward, R. B. In In the Alkaloids; Manske, R. H. F.; Holmes, H. L., Eds.; Academic Press: New York, 1953; Vol. 3, p 24; Verpoorte, R.; Schripsema, J.; Van der Leer, T. In In the Alkaloids. Chemistry and Pharmacology, Brossi, A., Ed.; Academic Press: New York, 1988; Vol. 34; Michael, J. P. In The Quinoline Alkaloids, In Rodd's Chemistry of Carbon Compounds, 2nd ed.; Sainsbury, M., Ed.; Elsevier: Amsterdam, 1998; 2nd suppl., part F and G, vol 4; 432. They are isolated en masse by extracting the bark of the cinchona tree, which is native to tropical regions. Outside of organic chemistry, the cinchona alkaloids have found wide use as food flavorings (for example as the bitter principle of tonic water) and in the treatment of malaria. Fletcher, D. C. J. Am. Med. Assoc. 1976, 236, 305; Mturi, N.; Musumba, C. O.; Wamula, B. M.; Ogutu, B. R.; Newton, C. R. J. C. CNS Drugs 2003, 17, 153. Additionally, their roles as ligands, chromatographic selectors, and NMR discriminating agents have been examined extensively over the past thirty years. Several reviews have been published on the catalytic chemistry of cinchona alkaloids over the past four decades. Pracejus, H. Forschr. Chem. Forsch. 1967, 8, 493; Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions; Prentice Hall: Englewood Cliffs, 1971; Wynberg, H. Top. Stereochem. 1986, 16, 87; Kacprzak, K.; Gawronski, J. Synthesis 2001, 7, 961.
These reactions appear to be broadly applicable to both research and industrial scale asymmetric synthesis of a wide variety of important chiral building blocks, such as hemi-esters, α-amino acids and α-hydroxy acids. Commercially available modified dimeric cinchona alkaloids (DHQD)2AQN and (DHQ)2AQN, have been identified recently by Deng and coworkers as enantioselective, recyclable catalysts for enantioselective alcoholyses of cyclic anhydrides. However, commercially available (DHQD)2AQN is expensive. For example, the commercial price (Aldrich Chemical Company) for a mole of (DHQD)2AQN is more than $100,000.00. Furthermore, the dimeric catalyst is not available in large quantity (e.g., in kilogram quantity). Therefore, stereoselective reactions using dimeric catalysts are not practical on a relatively large scale (>0.1 mol). Consequently, the development of a new generation of monomeric catalysts that is comparably effective to (DHQD)2AQN, but substantially less costly to produce, is of significant practical value.
Chiral metal and organic catalysts that possess both an acidic and a basic/nucleophilic structural moiety constitute an increasingly powerful platform for the development of asymmetric catalysis. The design and development of such bifunctional chiral catalysts that are efficient yet easily accessible continues to be a major challenge. Wynberg and coworkers demonstrated that natural cinchona alkaloids, via their C9-OH and amine groups, served as bifunctional chiral organic catalysts for enantioselective reactions by activating the nucleophile and electrophile, respectively. Wynberg, H., Hiemstra, H., J. Am. Chem. Soc., 1981, 103, 417. However, the enantioselectivity of various reactions catalyzed by natural cinchona alkaloids as chiral organic catalysts was usually modest. Hatakeyama and coworkers recently reported a rigid modified cinchona alkaloid that is readily accessible from quinidine. Hatakeyama, S. et al., J. Am. Chem. Soc., 1999, 121, 10219; Hatakeyama, S., Organic Lett., 2003, 5, 3103. The catalyst was found to be efficient for an enantioselective Morita-Baylis-Hillman (MBH) reaction. Both the C6′-OH and the amine groups are believed to be involved in the stabilization of the transition state of the enantioselective MBH reaction.
The nitroaldol reaction, or Henry reaction, constitutes an important class of C—C bond forming reactions that provides straightforward access to important synthetic intermediates from readily accessible nitroalkanes and carbonyl compounds. For reviews, see: Luzio, F. A. Tetrahedron 2001, 57, 915-945; Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York, 2001; and Seebach, D.; Beck, A. K.; Mukhopadhyay, T.; Thomas, E. Helv. Chim. Acta 1982, 65, 1101-1133. Due to its significance in organic synthesis, considerable efforts have been devoted to the development of efficient catalytic asymmetric nitroaldol reactions. For a recent review of catalytic asymmetric nitroaldol reactions, see: Palomo, C.; Oiarbide, M.; Mielgo. A.; Angew. Chem. Int. Ed. 2004, 43, 5442-5444. As mentioned above, the nitro group, often described as a “synthetic chameleon,” can serve as masked functionality to be further transformed after the addition has taken place. G. Calderari, D. Seebach, Helv. Chim. Acta 1995, 68, 1592-1604. The Nef reaction, the nucleophilic displacement, the reduction to amino group, the Myer reaction, and the conversion into a nitrile oxide are only a few examples of the transformations that nitro groups can undergo. H. W. Pinnick, Org. React. 1990, 38,655-792; J. U. Nef, Justus Liebigs Ann. Chem. 1894, 280, 263-291; R. Tamura, A. Kamimura, N. Ono, Synthesis 1991, 423-434; R. C. Larock, Comprehensive Organic Transformations, VCH, New York, 1989, pp. 411-415; A. K. Beck, D. Seebach, Chem. Ber. 1991, 124, 2897-2911; R. E. Maeri, J. Heinzer, D. Seebach, Liebigs Ann. 1995, 1193-1215; M. A. Poupart, G. Fazal, S. Goulet, L. T Mar, J. Org. Chem. 1999, 64, 1356-1361; A. G. M. Barrett, C. D. Spilling, Tetrahedron Lett. 1988, 29, 5733-5734; D. H. Loyd, D. E. Nichols, J. Org. Chem. 1986, 51, 4294-4298; V. Meyer, C. Wurster, Ber. Dtsch. Chem. Ges. 1873, 6, 1168-1172; M. J. Kamlet, L. A. Kaplan, J. C. Dacons, J. Org. Chem. 1961, 26, 4371-4375; T. Mukayama, T Hoshino, J. Am. Chem. Soc. 1960, 82, 5339-5342. A number of catalytic synthetic methods have been developed in recent years, making use of nitroalkenes even more attractive. A. G. M. Barret, G. G. Graboski, Chem. Rev. 1986, 86, 751-762; R. Ballini, R. Castagnani, M. Petrini, J. Org. Chem. 1992, 57, 2160-2162; G. Rosini, R. Ballini, M. Petrini, P Sorrenti, Synthesis 1985, 515-517. Consequently, several chiral metal complexes and a phase-transfer catalyst have been identified to be highly efficient catalysts for enantioselective nitroaldol reactions with aldehydes. Sasai, H.; Suzuki, T.; Arai, S.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418-4420; Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187-2209; Trost, B.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861-863; Trost, B.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett. 2002, 4, 2621-2623; Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692-12693; Palomo, C.; Oiarbide, M.; Laso, A.; Angew. Chem. Int. Ed. 2005, 44, 3881-3884; and Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054-2055.
In contrast to the substantial progress made with aldehydes, efforts to develop enantioselective nitroaldol reactions with ketones have met with limited success. Christensen, C.; Juhl, K.; Jørgensen, K. A.; Chem. Commun. 2001, 2222-2223; Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 4875-4881; Misumi, Y.; Bulman, R. A.; Matsumoto, K. Heterocycles 2002, 56, 599-606; Lu, S. F.; Du, D. M.; Zhang, S. W.; Xu, J. X. Tetrahedron: Asymmetry 2004, 15, 119-126; and Du. D. M.; Lu, S. F.; Fang, T.; Xu, J. X. J. Org. Chem. 2005, 70, 3712-3715. To date, only one catalyst system, consisting of a Cu-bisoxazoline complex and triethyl amine, has been identified to afford synthetically useful enantioselectivity for the addition of nitromethane to α-keto ethyl esters. However, in addition to requiring a catalyst loading of 20 mol % and the use of anhydrous conditions, both the yield and enantioselectivity of the reaction display a dependence on the structure of the α-keto ethyl esters. For example, the enantioselectivity was high for reactions with aryl α-keto ethyl esters bearing an electron-withdrawing group on the aromatic ring, it became moderate when the electron-withdrawing group was replaced with an electron-donating substituent. Depending on the steric bulk of the alkyl α-keto ethyl esters, the enantioselectivity could be either high or modest. For α-keto ethyl esters bearing an alkenyl group, synthetically useful enantioselectivity was not attainable.
Therefore, it is especially desirable to realize a catalytic asymmetric nitroaldol reaction that affords high enantioselectivity for a wide range of α-keto esters. Such a reaction, in combination with the synthetic versatility of the ester and the nitro groups, would provide enantioselective access to a broad range of optically active tertiary carbinols. Remarkably, in one aspect of the invention, bifunctional organic catalysts derived from either quinidine or quinine have been developed and utilized for catalytic asymmetric nitroaldol reactions.